1. Field of the Invention
The present invention relates generally to methods and formulations for minimizing spasticity in ex-vivo and in-vivo blood vessel grafts and more particularly to the minimization of spasticity though the administration of a spasticity minimizing agent solution to arterial grafts.
2. Description of the Background Art
As the patient population presenting with coronary artery disease (for example, but not limited to, those patients presenting with blocked coronary arteries) becomes older and 10% to 30% of these patients have to undergo cardiac re-operations involving replacement bypass grafts, there exists a need to identify new sources of bypass graft conduits and new treatments for the preparation of same.
Bypass graft conduits have traditionally been performed with venous grafts, typically pieces of veins from the patient's leg (generally the saphenous vein), which are harvested and then transplanted in a bypass procedure, typically a coronary bypass artery procedure. However, the use of arteries for bypass graft conduits has been increasing in frequency, these arteries generally having a more muscular media than that of veins and thus being able to withstand, on the average, higher blood pressures than that of venous grafts.
During the last 15 years, there as been a marked increase in the use of arterial conduits to perform coronary artery bypass grafting (CABG). The clinical and survival benefits of bilateral internal thoracic artery grafts have established them as conduits of first choice for CABG, whereas the radial artery has rapidly become the second most commonly used arterial conduit.
Blood vessel grafts, especially arterial grafts, commonly used in transplantations (bypass procedures) are prone to spasticity, i.e., vasospasm (the muscular media of the blood vessel wall having a tendency or increased tendency to undergo intermittent contraction) or “string sign” with use of vasopressor therapy both intra-operatively and post-operatively, and thus cause increased resistance and hence a decrease in blood flow through the arterial grafts. For example, the internal thoracic artery, like other arteries that are used for arterial grafts, has a capacity to undergo vasospasm or spasticity due to its inherent arterial nature of having more muscular media than venous blood vessels (veins). Such spasticity can result in a decrease in blood flow to the heart muscle resulting in angina, as well as possibly severe myocardial infarction or hypoperfusion. The spasticity of the artery can thus adversely affect the conduit's (graft's) long-term patency and can therefore result in the need to perform another coronary bypass procedure with a new graft or conduit within as few as three years. Specifically, radial artery bypass conduits are very prone to spasticity, causing increased resistance and decreased blood flow in coronary artery bypass grafts.
The radial artery is a versatile conduit, which can be harvested easily and safely, has handling characteristics superior to those of other arterial grafts, and comfortably reaches any coronary target. Several studies have reported superior patency of radial artery grafts compared with vein grafts at up to five years after CABG. Enthusiasm for widespread use of the radial artery as a conduit for CABG has, however, been tempered by its greater proclivity to spasm in the perioperative period.
Indeed, the radial artery was first suggested as a conduit (graft) for coronary artery surgery in 1973, but later was abandoned owing to a high failure rate (35% at two years post operation) of the graft, with such failures attributed primarily to vasospasm (spasticity). Later, the failure rate was reduced somewhat with the treatment of adding calcium-channel blockers and aspirin administered post-operatively. However, despite the use of the calcium-channel blockers, aspirin and vasodilators such as nitroglycerin, sodium nitroprusside and papaverine during the harvesting period of arterial grafts, vasospasm, hypoperfusion, and graft failure were still observed.
The tendency of the radial artery to spasticity (vasospasm) can thus result in severe post-operative myocardial hypoperfusion, as well as adversely affecting the grafts long-term patency. The capacity of the radial artery for vasospasm is several-fold greater than that of other arteries, for example the internal thoracic artery, because of its high muscular media and generally thicker arterial wall, and this spasticity/vasospasm risk is further increased in patients who require inotropic or vasoconstrictor therapy.
Various pharmacologic maneuvers have been recommended to reduce (minimize) the risk of radial artery vasospasm in the perioperative period, but all have significant limitations. Intravenous infusions of calcium channel blockers cause hypotension, bradycardia, and significant rhythm disturbances, whereas the topically applied agents, such as papaverine and nitroglycerin, have relatively short half-lives. The current pre and/or intra-operative treatment with papaverine, or other vasodilator agents, fails to either minimize, or provide a sustained inhibition of, spasticity (vasoconstriction) during and immediately after transplantation.
Thus, arterial grafts, and most particularly radial arterial grafts, have a greater tendency to spasticity or vasospasm due in part to the greater muscularity of arteries as compared to veins. For radial arteries, the increase of musculature in the arterial wall, the thicker media and a more dense organization of myocytes and less connective tissue than other arteries, such as the internal mammary artery, all combine to make the radial artery more susceptible to vasoactive substances, for example potassium, serotonin, and the alpha agonists norepinephrine and phenylephrine. As a result, arterial grafts, and radial artery grafts in particular, are at a greater risk for spasticity (vasospasm) during catecholamine surges that occur during cardiopulmonary bypass and post-surgical events (such as discontinuation of ventilation and removal of chest tubes) as well as during the administration of pressor agents to sustain the patient's blood pressure during the post-operative period.
Presently, phosphodiesterase inhibitors, which are vasodilator agents, such as papaverine, are used to reduce spasticity (i.e., attenuate or minimize vasospasm) of arterial grafts. However, papaverine treatments are also problematic in that they are limited by the temporary reduction in constrictor responses and seem to result in an overwhelmingly high risk of endothelial damage of the prospective arterial graft segments.
Finally, the problems of a greater tendency to spasticity or vasospasm and short term patency in internal thoracic arterial grafts has minimized the use of said artery in coronary bypass grafting and essentially mandated the use of ex-vivo procedures for coronary bypass grafting using harvested arterial grafts. Ex-vivo procedures for such harvested arterial grafts typically require the artery to be harvested to be removed from the body of a donor or patient and placed into a sterile environment, cooled down for transport of the artery from the operating room to a laboratory or other room (if attempts to minimize spasticity are performed), and thereafter warmed up again to approximately body temperature, while being provided with oxygen and maintained at proper pH (typically around pH 7.4) for transportation back to the operating room and implantation back into the body of the patient. The time requirements for such ex-vivo methods, in addition to sterility, oxygenation and cold/heat shock concerns to the harvested arterial graft, can be serious drawbacks and at the very least delay the transplantation or implantation of the harvested artery in a coronary bypass procedure.